טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentNahman Averbuch Hadas
SubjectMechanisms of Pain Modulation in Healthy Humans:
Physiological and Pharmacological Attributes
DepartmentDepartment of Medicine
Supervisor Professor David Yarnitsky
Full Thesis textFull thesis text - English Version


Abstract


Conditioned pain modulation (CPM) and offset analgesia (OA) are two pain modulation phenomena, which reflect endogenous analgesia capabilities of individuals and are instrumental in predicting clinical outcomes such as chronic pain development and treatment efficacy. The present study aimed to enhance the understanding of CPM and OA mechanisms focusing on: (i) neuroanatomical brain regions participating in these modulation effects, (ii) neurochemical aspects, specifically noradrenergic tone, (iii) effects of autonomic function and (iv) effects of psychological factors. For examining neuroanatomical regions, CPM and OA were tested in 13 healthy subjects during an fMRI scan. A distinct brain activation pattern was found for CPM and OA; during CPM, compared to OA, higher reduction in activations of brain regions associated with afferent nociceptive processing including the thalamus, putamen, posterior insula and the brainstem, was found. However, during OA, compared to CPM, greater activation in brain regions associated with the modulation of nociceptive processing such as the anterior insula and brainstem was observed. These suggest that CPM and OA engage different mechanisms to induce pain modulation. For examining noradrenergic tone, 40 healthy subjects were tested before and after alpha2 agonist (clonidine) or placebo administration. Reducing noradrenergic tone by alpha2 agonist administration had no effect on the capacity of CPM and OA. However, following alpha2 agonist administration, the association found between higher parasympathetic activity and more efficient pain inhibitory response was more prominent for OA than CPM. No such relationships were found in the placebo group.  For examining the effects of non-perturbed autonomic function on pain modulation, a different analysis was obtained from the former cohort. Only CPM was found to be related with autonomic function such that higher parasympathetic activity was correlated with higher CPM capacity.  This relationship was found only in men. For examining the effect of psychological factors, we conducted a comprehensive meta-analysis that showed relationships between CPM capacity and the level of psychological factors. These relations are complex and depend on the characteristics of the CPM paradigm, particularly the Test stimulus modality. It was found that efficiency of CPM induced by mechanical test stimulus was associated with anxiety, that of heat stimuli with depression, and that of electrical stimuli with pain catastrophizing.

Our findings suggest that CPM and OA are two distinct pain modulation phenomena. The different brain activation patterns may suggest that OA is mediated via brain regions involved in pain modulation while it is possible that CPM is involving mostly spinally mechanisms. In addition the different effect of noradrenalin tone on CPM and OA responses may suggest that OA efficiency is indirectly dependent on noradrenalin tone via the activation of the autonomic system; according to the activation pattern found for OA we speculate that the insula may mediate this relationship. Furthermore, the gender differences in the relationships between CPM and parasympathetic function may suggest sex hormones involvement in the CPM response although this was not tested. Moreover, different CPM paradigms show by meta-analysis, engage different mechanisms with different influences by psychological and neurochemical factors. 


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